Parameters that govern the regulation of immunoglobulin delta heavy-chain gene expression.

Tisch, Roland; Kondo, Naomi; Hozumi, Nobumichi

doi:10.1128/mcb.10.10.5340

Cited by 9 publications

(8 citation statements)

References 34 publications

(26 reference statements)

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“…Therefore it appears that there is a polymerase pause site just downstream of this region that causes variations in the extent of polymerase entrapment. The best candidate for this site is the conotical MAZ binding site (23) located 200 bp downstream of the µM poly(A) site within a region previously documented to be a polymerase unloading site in tumor cells (4,52). The termination of transcription close to a pause site located some distance from the polyadenylation site is consistent with a model whereby polymerase activates polyadenylation (46) by continued association with these processing factors (45).…”

Section: Discussionsupporting

confidence: 68%

Differential regulation of transcription termination occurring at two different sites on the μ–δ gene complex

Kim¹,

Qiu²,

AbuOdeh³

et al. 1999

International Immunology

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The progression of polymerases across the micro-delta Ig heavy chain gene complex is characterized by two termination events occurring at different sites on the transcription unit and at different times during B cell differentiation. We have utilized two mouse strains to analyze the regulatory determinants for these events in primary B cells. In the transgenic pmicro.microdeltaRatt strain a 1160 bp intervening DNA segment (the att site) has been inverted. This mutation results in the abrogation of transcription termination that occurs in early B cells. Using a novel method that takes advantage of an internal ribosome entry site we have further restricted the size of the segment that is needed for inducing transcription termination in transfectants. This 200 bp termination-inducing sequence operates in tumor equivalents of early but not mature B cells and the activity is correlated with differential binding of nuclear proteins. To explore the regulatory basis for the change in site of transcription termination upon B cell activation we have examined the microS-/- deletion mutant strain in which the microS poly(A) site has been eliminated. The results suggest that polyadenylation at the microS site plays a dominant but not exclusive role in regulating transcription termination in activated B cells.

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Section: Discussionsupporting

confidence: 68%

Differential regulation of transcription termination occurring at two different sites on the μ–δ gene complex

Kim¹,

Qiu²,

AbuOdeh³

et al. 1999

International Immunology

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“…The evidence above, combined with earlier models for Ighd expression (12,13,31), leads us to propose the following simple hypothesis for ZFP318-dependent IgD expression (Fig. S1).…”

Section: Discussionmentioning

confidence: 99%

“…First, differential expression of IgD during B-cell maturation has been shown to occur at the level of mRNA production (12,13,(29)(30)(31) Second, the ZFP318 zinc fingers are of the U1 type defined by the RNA-binding zinc finger in the spliceosomal U1C protein (25,32) and of the zf-C2H2_JAZ superfamily that bind double-stranded RNA or RNA-DNA hybrids (33). Third, both the long and short isoforms of ZFP318 accumulate selectively in the nucleus, with the short isoform localized to subnuclear speckles that contain histone deacetylase 2 (HDAC2) and are adjacent to nuclear speckles containing serine/arginine-rich splicing factor 2 (SRSF2, .…”

Section: Discussionmentioning

confidence: 99%

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

Enders¹,

Short²,

Miosge³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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IgD and IgM are produced by alternative splicing of long primary RNA transcripts from the Ig heavy chain (Igh) locus and serve as the receptors for antigen on naïve mature B lymphocytes. IgM is made selectively in immature B cells, whereas IgD is coexpressed with IgM when the cells mature into follicular or marginal zone B cells, but the transacting factors responsible for this regulated change in splicing have remained elusive. Here, we use a genetic screen in mice to identify ZFP318, a nuclear protein with two U1-type zinc fingers found in RNA-binding proteins and no known role in the immune system, as a critical factor for IgD expression. A point mutation in an evolutionarily conserved lysine-rich domain encoded by the alternatively spliced Zfp318 exon 10 abolished IgD expression on marginal zone B cells, decreased IgD on follicular B cells, and increased IgM, but only slightly decreased the percentage of B cells and did not decrease expression of other maturation markers CD21, CD23, or CD62L. A targeted Zfp318 null allele extinguished IgD expression on mature B cells and increased IgM. Zfp318 mRNA is developmentally regulated in parallel with IgD, with little in pro-B cells, moderate amounts in immature B cells, and high levels selectively in mature follicular B cells. These findings identify ZFP318 as a crucial factor regulating the expression of the two major antibody isotypes on the surface of most mature B cells.IgHm | IgHd | immunoglobulin isotype |

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“…This element might also have an impact on transcriptional readthrough into the C␦ exons, which are located downstream from the IgM constant region exons and are spliced into the Ig mRNA to produce IgD-encoding mRNA (6). IgD expression is down-regulated, both in early B cells and in plasma cells, because transcription terminates before reaching the C␦ exons (47,(54)(55)(56). A comparison of the transcriptional run-on profiles of B cells and plasma cells expressing the s poly(A) site deletions shown here, as well as genes containing pause site mutations, may shed some light on these possibilities.…”

Section: Discussionmentioning

confidence: 99%

An RNA Polymerase Pause Site Is Associated with the Immunoglobulin μs Poly(A) Site

Peterson

Bertolino

Davis

2002

Molecular and Cellular Biology

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Immunoglobulin alternative RNA processing is regulated during B-cell maturation and requires balanced efficiencies of the competing splice (m) and cleavage-polyadenylation (s) reactions. When we deleted sequences 50 to 200 nucleotides beyond the s poly(A) site, the s/m mRNA ratio decreased three-to eightfold in B, plasma, and nonlymphoid cells. The activity could not be localized to a smaller fragment but did function in heterologous contexts. Our data suggest that this region contains an RNA polymerase II pause site that enhances the use of the s poly(A) site. First, known pause sites replaced the activity of the deleted fragment. Second, the fragment, when placed between tandem poly(A) sites, enhanced the use of the upstream poly(A) site. Finally, nuclear run-ons detected an increase in RNA polymerase loading just downstream from the s poly(A) site, even when the poly(A) site was inactivated. When this fragment and another pause site were inserted 1 kb downstream from the s poly(A) site, they no longer affected the mRNA expression ratio, suggesting that pause sites affect poly(A) site use over a limited distance. Fragments from the immunoglobulin A gene were also found to have RNA polymerase pause site activity.Elements that modulate gene expression by altering RNA polymerase elongation (reviewed in references 9, 35, 43, and 49) have been identified near the 5Ј end of genes (e.g., myc and human immunodeficiency virus) (18,20,26,27), within the coding region of genes (e.g., histone H3.3 and apolipoprotein A-I) (22,37,46), and downstream from some (3, 14), but not all (51), cleavage-polyadenylation [poly(A)] sites. The elements found downstream from the ␣ globin (14) and complement C2 (3) poly(A) sites were shown to contribute to transcriptional termination. The ␣ globin element is contained within a 92-bp fragment that is located about 300 nucleotides (nt) downstream from the ␣ globin poly(A) site (14). The C2 element is a 156-bp fragment that begins just downstream from the C2 poly(A) site; despite its close proximity, it is not required for efficient use of the C2 poly(A) site (3). These elements were called RNA polymerase pause sites because they appeared to have a kinetic affect on RNA polymerase II transcription (3, 14); when placed between two competing reactions, their effect on gene expression was consistent with these elements causing RNA polymerase to pause or slow its elongation rate. This was true when they were placed between tandem poly(A) sites (3,14), between tandem promoters (13), and between a regulated exon and its intronic regulatory region (38). In addition, in nuclear run-on assays, which measure RNA polymerase loading along a transcription unit, an increase in RNA polymerase loading was seen over these elements, again suggesting that RNA polymerase was being slowed or temporarily paused, so there was a higher probability of finding RNA polymerase molecules over those regions (3,14). More recently, the activity of these pause sites and their effect on upstream poly(A) sites was examined in...

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Parameters that govern the regulation of immunoglobulin delta heavy-chain gene expression.

Cited by 9 publications

References 34 publications

Differential regulation of transcription termination occurring at two different sites on the μ–δ gene complex

Differential regulation of transcription termination occurring at two different sites on the μ–δ gene complex

Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively splicedIghproduct made by mature B lymphocytes

An RNA Polymerase Pause Site Is Associated with the Immunoglobulin μs Poly(A) Site

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